This proposed Mentored Clinical Scientist Development Award (K08) is a resubmission of an application aimed at functionally analyzing Alzheimer's disease (AD) positional candidate genes encoding proteins that are biologically implicated in beta-amyloid precursor protein (APP)-related pathways. In accord with the very helpful and constructive comments of the Reviewers, in the revised application, we have proposed fewer, more focused, hypothesis-driven experiments. The proposed K08 application, consisting of bench research, coursework, seminar series and professional conferences, will allow the applicant to: 1) gain experience in genetic, molecular and cellular biological aspects of AD; and 2) develop into an independent researcher with unique multidisciplinary skills for the study of AD, and other dementia disorders such as Post Operative Cognition Disorder (POCD). Dr. Rudolph Tanzi will supervise the applicant in performing the proposed studies in the Genetics and Aging Research Unit in Mass General Institute for Neurodegenerative Disease at Massachusetts General Hospital in Boston, an AD research hub consisting of a dynamic, interactive group of scientists in genetics, molecular biology and cellular biology. Alzheimer's disease (AD) is one of the greatest public health problems in the U.S., and its impact will only increase with demographic changes anticipated in the coming decades. Genetic evidence, confirmed by neuropathological and biochemical studies, indicates that excessive A-beta peptide generated from amyloidogenic processing of the beta-amyloid precursor protein (APP) plays a fundamental role in the AD neuropathogenesis. However, the functional roles of the positional AD candidate genes on APP processing and gamma-secretase activity following reduction in their expression are entirely unknown. This gap of knowledge impedes the progress toward fully understanding the functional roles of these genes on APP processing and A-beta production, a putative step of AD neuropathogenesis. The goal of this proposal is to primarily conduct RNA interference (RNAi)- and over-expression-based experiments to categorize these positional AD candidate genes according to their effects on APP processing. The genes, alterations (reductions and over-expression of their expression influence APP processing), will be further studied to determine the molecular mechanisms underlying these effects, especially, the extent to which alterations in the expression for these genes affect gamma-secretase activity leading to changes in APP processing and, ultimately, A-beta production. Specifically, the genes to be individually silenced by RNAi are positional candidate AD genes, earmarked by a recently completed full genome screen, that encode APP C-terminal adapter proteins. These studies should ultimately facilitate the development of strategies for prevention and treatment of AD.